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PIKfyve, a class III lipid kinase, is required for TLR-induced Type i IFN production via modulation of ATF3

Cai, Xinming and Xu, Yongyao and Kim, You-Me and Loureiro, Joe and Huang, Qian (2014) PIKfyve, a class III lipid kinase, is required for TLR-induced Type i IFN production via modulation of ATF3. Journal of Immunology, 192 (7). pp. 3383-3389. ISSN 1550-6606

Abstract

Type I IFN plays a key role in antiviral responses. It also has been shown that deregulation of type I IFN expression following abnormal activation of TLRs contributes to the pathogenesis of systemic lupus erythematosus. In this study, we find that PIKfyve, a class III lipid kinase, is required for endolysosomal TLR-induced expression of type I IFN in mouse and human cells. PIKfyve binds to phosphatidylinositol 3-phosphate and synthesizes phosphatidylinositol 3,5-bisphosphate, and plays a critical role in endolysosomal trafficking. However, PIKfyve modulates type I IFN production via mechanisms independent of receptor and ligand trafficking in endolysosomes. Instead, pharmacological or genetic inactivation of PIKfyve rapidly induces expression of the transcription repressor ATF3, which is necessary and sufficient for suppression of type I IFN expression by binding to its promoter and blocking its transcription. Thus, we have uncovered a novel phosphoinositide-mediated regulatory mechanism that controls TLRmediated induction of type I IFN, which may provide a new therapeutic indication for the PIKfyve inhibitor. The Journal of Immunology, 2014, 192: 3383-3389. © Copyright 2014 by The American Association of Immunologists, Inc. All rights reserved.

Item Type: Article
Date Deposited: 01 Dec 2017 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/20607

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